1区 · 医学
Article
作者: Nath, Karthik ; Farzana, Tasmin ; Bermudez, Vladimir P. ; Wang, Xiuyan ; Sen, Filiz ; Fitzgerald, Lisa ; Purdon, Terence J. ; Hassoun, Hani ; Park, Jae H. ; Hultcrantz, Malin ; Auclair, Romany ; Wilcox, Jessica A. ; Dogan, Ahmet ; Santomasso, Bianca D. ; Shah, Urvi A. ; Sikder, Devanjan ; Landa, Jonathan ; Devlin, Sean M. ; Russo, Douglas ; Smith, Eric L. ; Usmani, Saad Z. ; Shah, Gunjan L. ; Landgren, Ola ; Tan, Carlyn R. ; Rivière, Isabelle ; Giralt, Sergio A. ; Carstens, Elizabeth J. ; Hosszu, Kinga ; Lesokhin, Alexander ; Mead, Elena ; Mailankody, Sham ; Senechal, Brigitte ; Korde, Neha ; Roshal, Mikhail ; Brentjens, Renier J. ; Cadzin, Briana ; Diamonte, Claudia ; McAvoy, Devin P.
BACKGROUND:B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model.
METHODS:In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy.
RESULTS:A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells.
CONCLUSIONS:The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).